The outcome of long-term benzodiazepine hypnotic therapy has been investigated in a group of elderly patients in the community; 220 receiving nitrazepam and 33 flurazepam. The estimated duration of therapy was as long as 15 years in some cases. More than half were taking doses greater than 5 mg and 15 mg, respectively, the majority on a regular nightly basis in accordance with the instructions on containers. The plasma concentrations of nitrazepam and the active desalkyl metabolite of flurazepam correlated positively with weight-related dose. In the case of desalkyl-flurazepam, but not nitrazepam, the levels were substantially higher than those previously reported in young individuals. There was sustained patient satisfaction with the effectiveness of the hypnotics and, despite the high plasma levels, little subjective or objective evidence of unwanted sedation, confusion or unsteadiness. The findings of the survey suggest the development of both pharmacodynamic tolerance to the unwanted sedative effects of these drugs and a degree of dependence in long-term recipients.
1 The pharmacokinetics of the benzodiazepine hypnotic, loprazolam (1.0 mg orally), and the pharmacodynamic response to single oral doses (0.5 mg and 1.0 mg) have been compared in young and elderly healthy volunteers.2 No difference between the groups in peak plasma concentration (Cma,) or in the time to peak (tmax) was found, but the elimination half-life t½,2z and area under the plasma concentration-time curve (AUC) were significantly greater in the elderly group. 3 The immediate effects of loprazolam on all three performance tests used (postural sway, critical flicker fusion threshold (CFFT) and choice reaction time (CRT)) and on subjective sedation tended to be more pronounced in the elderly subjects, though intersubject variability in response was high in both groups. The corresponding plasma concentrations did not differ significantly between the two groups. 4 The higher (1.0 mg) dosage was associated with significant residual (11 h) impairment of standing steadiness in the elderly subjects. No other hangover effects were observed. 5 The results are compatible with previous evidence of increased 'sensitivity' to benzodiazepines in the elderly and suggest that a lower (0.5 mg) starting dose of loprazolam would be appropriate for older recipients. 6 Further investigation would be necessary to establish whether clinically relevant accumulation of loprazolam occurs in the elderly following repeated dosage.
The effects of single 10 mg oral doses of the antidepressant mianserin on psychomotor performance, subjective sedation and supine and standing blood pressure were compared in ten young and nine elderly healthy volunteers. Immediate and residual sedation following this subtherapeutic dose was readily detected in both groups. In contrast to previous studies with benzodiazepines, the sedation effect was not accentuated in the older subjects. Subjective awareness of sedation was significant in the young but not, however, in the elderly. "First-dose" postural hypotension, presumably due to post-synaptic alpha-blockade also occurred in young subjects only. Caution may be needed on initial dosage of mianserin in young individuals who drive or undertake skilled tasks and in the elderly who may be unaware of psychomotor impairment. The reported alpha 2 receptor selectivity of mianserin might explain the lack of postural effects in the elderly, and might constitute a potentially useful characteristic in the development of new compounds.
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